PKC inhibitor, N-Benzoyl staurosporine, paradoxically induces megakaryocytic differentiation and possesses therapeutic potential in human chronic myeloid leukemia.

摘要: B243 Background: Previous research has shown activation of PKC leads to differentiation progenitor cells into megakaryocytes. N-Benzoyl staurosporine, derived from naturally occurring inhibits multiple isoforms the serine/threonine protein kinase C (PKC). In preclinical studies, staurosporine showed broad antiproliferative activity against various tumor cell lines, including acute myeloid leukemia. We explored its therapeutic effect on chronic leukemia (CML) and found that in addition inducing apoptosis inhibiting growth CML cells, paradoxically promoted megakaryocytes.
 Materials methods: Human K562 line was used as an vitro model. MTT assay for assessment viability. Liu’s dyes immunofluorescent mAbs alpha-tubulin DAPI were morphological observation. DNA histogram surface markers examined by using flow cytometry. C-mpl mRNA expression evaluated RT-PCR.
 Results: inhibited a dose- time-dependent manner with IC50 around 0.5 μM. Morphological changes such enlarged contour nuclei characteristic megakaryocytes noted more than half (0.5 - 1.0 μM)-treated cells. shows arrested marked 2n, 4n 8n content. Surface megakaryocytic marker CD61 enhanced contrast, erythrocytic glycophorin A treatment staurosporine. The c-mpl, gene encoding thrombopoietin receptor, increased. These results indicate may induce differentiate toward Both activator 12-O-tetradecanoyl phorbol-13-acetate inhibitor expressed differentiating similar indicating via PKC-independent pathway. Furthermore, at higher dose (1.0 μM) induced smaller population demonstrated increase hypodiploid fraction Conclusion: contrast previous research, where causes differentiation, here we observed paradoxical phenomenon known (N-Benzoyl staurosporine) promoting also lesser extent, caused human It have potential novel agent CML.